The long-term goal of the proposed study is to elucidate the mechanism by which neuroactive insecticides exert their toxic actions. The specific aims of the proposed renewal application are to elucidate the physiological mechanisms that underlie the selective toxicity of several selected newer insecticides between mammals and insects. Most insecticides are much more toxic to insects than to mammals, and the mechanism of selective toxicity lies in many cases in differential actions on the target neuroreceptors/ion channels. Although recent developments and applications of molecular biology and genetics techniques have identified the molecular structures such as amino acid compositions of target receptors/channels that are deemed responsible for differential actions, almost nothing is known about how the differential actions are brought about as a result of the difference in molecular structures. Our working hypothesis is that the differential actions of insecticides on the target receptor/channels of mammals and insects could be caused by some difference in the kinetics of receptors/channels. For example, insecticide modification of the channel may be dependent upon the channel open or closed state, the kinetics of insecticide binding and unbinding, the temperature coefficient, etc. In order to elucidate the physiological mechanisms of selective toxicity, patch clamp data on the kinetics of receptors/channels and those of insecticide modification will be compared between rat and cockroach neurons for fipronil modulation of GABA receptors, imidacloprid modulation of neuronal nicotinic acetylcholine receptors (nnAChRs), spinosad modulation of nnAChRs and GABA receptors, and indoxacarb modulation of sodium channels, nnAChRs and GABA receptors. The results thus obtained are expected to answer the question of how selective toxicity between mammals and insects can be explained in terms of the differential actions on the target receptors/channels. This information will significantly contribute to the development of newer therapeutic means of insecticide intoxication of humans and of more effective and safer insecticides.